Aldols propionate aldol reactions

For the propionate aldol reaction the Li enolate (7), generated by deprotonation of 2,6-dimethylphenyl propionate with Lithium Diisopropylamide in EtiO, was chosen. Transmetalation with 1.25 equiv of an ethereal solution of (1) takes 24 h at —78 °C. The completion of this step is evident by the disappearance of racemic anti-a do (9) in favor of optically active yw-isomer (10) (91-98% ee) upon reaction with an aldehyde (RCHO) and aqueous workup. At this point, 3-11% of anri-aldol (9) remaining in the reaction mixture is optically active as well (eq 2). This awri-isomer (9) (94-98% ee) becomes the major product if the reaction mixture, containing the putative ( )-titanium enolate derived from (7), is warmed for 4-5 h to —30°C before reaction with an aldehyde (RCHO) again at —78 °C. Isomerization to the (Z)-titanium enolate is a possible explanation of this behavior. Some substrates, aromatic and unsaturated aldehydes, behave exceptionally, as a high proportion of yn-isomer (10) (19-77%) of lower optical purity (47-66% ee) is formed in addition to (9) (94-98% ee). After hydrolysis of the acetonide (6) the products (9/10) are isolated and separated by chromatography in 50-87% yield. The reactions of pivalaldehyde (R = r-Bu) are sluggish at —78°C and have therefore been carried out at —50 to —30°C. 

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones, a-siloxy ketones, boron enolates with chiral ligands, as well as tin enolates. Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of 0-silyl ketene acetals. Most of these reactions afford s yw-aldols good methods for the anri-isomers have only become available recently. ... 

Nelson SG, Wan Z (2000) Catalytic asymmetric propionate Aldol reactions via acyl halide — aldehyde cyclocondensations. Org Lett 2 1883-1886... 

Aldol reaction of campholenic aldehyde with propionic aldehyde yields the intermediate conjugated aldehyde, which can be selectively reduced to the saturated alcohol with a sandalwood odor. If the double bond in the cyclopentene ring is also reduced, the resulting product does not have a sandalwood odor (161). Reaction of campholenic aldehyde with -butyraldehyde followed by reduction of the aldehyde group gives the aHyUc alcohol known commercially by one manufacturer as Bacdanol [28219-61 -6] (82). 

Silyloxy)alkenes were first reported by Mukaiyama as the requisite latent enolate equivalent to react with aldehydes in the presence of Lewis acid activators. This process is now referred to as the Mukaiyama aldol reaction (Scheme 3-12). In the presence of Lewis acid, anti-aldol condensation products can be obtained in most cases via the reaction of aldehydes and silyl ketene acetals generated from propionates under kinetic control. 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

Covalently bonded chiral auxiliaries readily induce high stereoselectivity for propionate enolates, while the case of acetate enolates has proved to be difficult. Alkylation of carbonyl compound with a novel cyclopentadienyl titanium carbohydrate complex has been found to give high stereoselectivity,44 and a variety of ft-hydroxyl carboxylic acids are accessible with 90-95% optical yields. This compound was also tested in enantioselective aldol reactions. Transmetalation of the relatively stable lithium enolate of t-butyl acetate with chloro(cyclopentadienyl)-bis(l,2 5,6-di-<9-isopropylidene-a-D-glucofuranose-3-0-yl)titanate provided the titanium enolate 66. Reaction of 66 with aldehydes gave -hydroxy esters in high ee (Scheme 3-23). 

These first examples of the catalytic asymmetric aldol reaction not only provided first results that could be utilized for such transformations but also highlighted the problems that had to be overcome in further elaborations of this general method. It was shown that truly catalytic systems were required to perform an enantioselective and diastereoselective vinylogous aldol reaction, and it became obvious that y-substituted dienolates that serve as propionate-acetate equivalents provide an additional challenge for diastereoselective additions. To date, the latter problem has only been solved for diastereoselective additions under Lewis acid catalysis (vide infra) (Scheme 4, Table 3). 

The development of enantioselective aldol reactions has been widely studied in conjunction with the synthesis of natural products. Highly enantioselective aldol reactions have been achieved by employing chiral enolates of ethyl ketones and propionic acid derivatives.(1) On the other hand, achieving high asymmetric induction in the asymmetric aldol reaction of methyl ketones is still a problem.(2)... 

This procedure demonstrates a particularly effective method for controlling the relative and absolute stereochemistry of the aldol reaction. It is quite general in scope. Alkyl-, aryl, and a,6-unsaturated aldehydes all give good results. In addition to chiral propionates, a range of related aldol reactions may be carried out. For example, the analogous aldol reactions of thioalkyl, benzyloxy, or haloacetate, as well as succinate- and crotonate-derived carboximides, have been reported. 

Some of the most impressive advances in the area of catalytic, enantioselective aldol addition reactions have taken place in the development of catalytic methods for enantioselective acetate aldol additions, a reaction type that has long been recalcitrant. Thus, although prior to 1992 a number of chiral-auxiliary based and catalytic methods were available for diastereo- and enantiocontrol in propionate aldol addition reactions, there was a paucity of analogous methods for effective stereocontrol in the addition of the simpler acetate-derived enol silanes. However, recent developments in this area have led to the availability of several useful catalytic processes. Thus, in contrast to the state of the art in 1992, it is possible to prepare acetate-derived aldol fragments utilizing asymmetric catalysis with a variety of transition-metal based complexes of Ti(IV), Cu(II), Sn(II), and Ag(I). 

Impressive advances in catalytic, enantioselective propionate aldol addition reactions have also been documented since 1992. Mikami has described a Ti(lV) catalyst readily prepared from BINOL and TiC O Pr. A propionate aldol addition process by Evans utilizes complexes prepared with bisoxazoline ligands and Sn(II) and Cu(II). In analogy to the acetate aldol... 

Aldol reactions of propionate esters with aldehydes proceed more readily when promoted by the more Lewis acidic bromoborane (R,R)-5. This reagent is prepared... 

The stereochemical course of the aldol reaction can be controlled by the judicious selection of the enolization reagents. Treatment of propionate esters with <7-Hex2BOTf and triethylamine produced anti-aldol products, and that of with Bu2BOTf and diisopropylethylamine selectively gave syn-aldol products after reaction with aldehydes (Equation (180)).684 685 Complementary anti- and yy/z-selective asymmetric aldol reactions were also demonstrated in structurally related chiral norephedrine-derived propionate esters (Equation (181)).686... 

An effective control of the simple diastereoselectivity in boron-mediated aldol reactions of various propionate esters (162) was achieved by Abiko and coworkers (equation 45) °. They could show that under usual enolization conditions (dialkylboron triflate and amine) enol borinates are formed, which allowed the selective synthesis of 5yw-configured aldol products (Table 11). The enolization at low temperature (—78 °C) generated a (Z)-enolate selectively, which afforded mainly the syn diastereomer 164 after reaction with isobu-tyraldehyde (163), following a Zimmerman-Traxler transition-state. The anti diastereomer 164 instead was obtained only in small amounts (5-20%). 

This technology has been apphed as part of the total synthesis of myx-alamide A (Scheme 56) [139]. The stereoselective aldol reaction between aldehyde 218 and the propionate 219 dehvered, after reduction, protection, and acylation, ester 220 as a single isomer. After -silyl ketene acetal formation a [3,3]-sigmatropic rearrangement accompanied by 1,3-chirality transfer took place. This, together with the uniform prochirality at the double bonds of the... 

Aldol Addition. A catalyst generated upon treatment of Cu(OTf)2 with the (5,5)-r-Bu-box ligand has been shown to be an effective Lewis acid for the enantioselective Mukaiyama aldol reaction. The addition of substituted and unsubstituted enolsilanes at -78 °C in the presence of 5 mol % catalyst was reported to be very general for various nucleophiles, including silyl dienolates and enol silanes prepared from butyrolactone as well as acetate and propionate esters. 

Mukaiyama aldol reactions of silylketene acetal and pyruvate ester (eq 14) in the presence of 10 mol % Cu[(5,5)-/-Bu-box] (OTf)2 catalyst furnish the corresponding aldol product in excellent enantiomeric excess (98%). Furthermore, the addition reactions of ketene acetals derived from /-butyl thioacetate and ben-zyloxyacetaldehyde with only 5 mol % catalyst afford the aldol product in 91% ee (eq 15). It is also noteworthy that the addition of both propionate-derived (Z)- and ( )-silylketene acetals stereoselectively forms the jyn-adduct in 97% and 85% ee, respectively. 

Analogous with the previous results of enol silyl ethers of ketones, nonsubstituted ketene silyl acetals are found to exhibit lower levels of stereoregulation, while the propionate-derived ketene silyl acetals display a high level of asymmetric induction. The reactions with aliphatic aldehydes, however, resulted in a slight reduction in optical and chemical yields. With phenyl ester-derived ketene silyl acetals, syn adducts predominate, but the selectivities are moderate in most cases in comparison with the reactions of ketone-derived silyl enol ethers. Exceptions are a,p-unsaturated aldehydes, which revealed excellent diastereo- and enantioselectivities. The observed syn selectivity and re-face attack of nucleophiles on the carbonyl carbon of aldehydes are consistent with the aforementioned aldol reactions of ketone-derived enol silyl ethers. 

Aldol Reactions of Ester Derivatives. The Titanium(IV) C/tlor/dc-catalyzed addition of aldehydes to 0-silyl ketene acetals derived from acetate and propionate esters proceeds with high stereoselectivity. Formation of the silyl ketene acetal was found to be essential for high diastereoselectivity. Treatment of the silyl ketene acetal, derived from deprotonation of the acetate ester with LICA in THF and silyl trapping, with a corresponding aldehyde in the presence of TiCU (1.1 equiv) afforded the addition products in 93 7 diastereoselectivity and moderate yield (51-67%). Similarly, the propionate ester provides the anti-aldol product in high antilsyn selectivity (14 1) and facial selectivity (eq 4). 

Asymmetric Aldol Reactions. Reaction of (1) with Boron Tribromide in CH2CI2 affords, after removal of solvent and HBr, a complex (5) useful for the preparation of chiral enolates (eq 5). Complex (5) is moisture sensitive and is generally prepared immediately before use. For propionate derivatives, either syn or, less selectively, anti aldol adducts may be obtained by selection of the appropriate ester derivative and conditions. Thus reaction of f-butyl propionate with (5) and triethylamine produces the corresponding E 0) enolate, leading to formation of anti aldol adducts upon addition to an aldehyde (eq 6). Selectivities may be enhanced by substitution of the t-butyl ester with the (+)-menthyl ester. Conversely, reaction of 5-phenyl thiopropionate with (5) and Diisopropylethylamine affords the corresponding Z(0) enolates and syn aldol products (eq 7). ... 

Enantioselective Aldol Reactions. The use of 1 for generating two contiguous stereocenters via an asymmetric aldol condensation has also been investigated,but only with marginal success. For example, reaction of the lithium enolate derived from tert-butyl propionate with the /Y-lithio derivative of 1, followed by condensation with benzaldehyde, provided a mixture of anti and syn aldol products in poor-to-modest % ee (eq 8). 

The 3f-promoted asymmetric aldol reaction of a variety of aldehydes with a silyl nucleophile derived from phenyl propionate E isomer, 98 %) resulted in moderate nnh-diastereoselectivity with relatively low enantioselectivity. With pivalaldehyde and the silyl nucleophile derived from ethyl propionate ElZ = 85 15), on the other hand, the syn isomer was obtained as a major product (22 1) with 96 % ee (Eq. 57) [43g]. 

In the reactions with the propionate derivatives, which provide synthetically useful a-methyl-/3-hydroxy ester derivatives, a combination of Sn(OTf)2, (5)-l-methyl-2-[(A(-l-naphthylamino)methyl]pyrrolidine, and Bu3Sn(OAc)2 gives better results (Eq. 20) [33,35]. The asymmetric aldol reactions proceed with higher enantioselectivity and, in addition, the reactions proceed faster with Bu3Sn(OAc)2 as an additive than with BusSnE A wide variety of aldehydes including aliphatic, aromatic, and a,/3-unsatu-rated aldehydes can be used in this reaction, and the aldol adducts are always obtained in high yields with perfect syn selectivity the enantiomeric excesses of these syn adducts are > 98 %. 

New auxiliaries and reaction methods are now available for the stereoselective synthesis of all members of the stereochemical family of propionate aldol additions. These also include improvements on previously reported methods that by insightful modification of the original reaction conditions have led to considerable expansion of the versatility of the process. In addition to novel auxiliary-based systems, there continue to be unexpected observations in diastereoselective aldol addition reactions involving chiral aldehyde/achiral enolate, achiral aldehyde/chir-al enolate, and chiral aldehyde/chiral enolate reaction partners. These stereochemical surpri.ses underscore the underlying complexity of the reaction process and how much we have yet to understand. 

In addition to the acetate aldol problem, stereoselective aldol additions of substituted enolates to yield 1,2-anti- or f/treo-selective adducts has remained as a persistent gap in asymmetric aldol methodology. A number of innovative solutions have been documented recently that provide ready access to such products. The different successful approaches to anri-selective propionate aldol adducts stem from the design of novel auxiliaries coupled to the study of metal and base effects on the reaction stereochemistry. The newest class of auxiliaries are derived from A-arylsulfonyl amides prepared from readily available optically active vicinal amino alcohols, such as cw-l-aminoindan-2-ol and norephedrine. 

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